.omega.-hydroxy acids are valuable intermediates in manufacture of ceramide 1. Ceramides are lipids found in skin which form a water barrier in skin preventing water loss from the skin. Several species of natural ceramides have been identified. Ceramide 1 is one of the major ceramides found in skin. Ceramide 1 must be obtained either through a lengthy process involving the extraction of the ceramide from natural sources or via a synthetic route. Synthetic routes to ceramide 1 involve reacting an .omega.-hydroxy acid with sphingosine and linoleic acid. See e.g., WO 93/22281 (Unilever). A cost-effective synthesis of .omega.-hydroxy acids is desirable, in order to lower the cost of ceramide 1 manufacture.
.omega.-hydroxy acids may also be used in skin treatment and cosmetic compositions, without prior conversion to ceramides. Recent research demonstrates that topical application of .omega.-hydroxy acids stimulates ceramide production in the epidermis, leading to an increase in the level of ceramides in the skin.
.omega.-hydroxy acids are also key raw materials in the manufacture of fragnances and various polymers.
An .omega.-hydroxy acid may be obtained naturally or by a synthetic route.
WO 93/22,28 discloses the synthesis of ceramide 1 and .omega.-hydroxytricotanoic acid. .omega.-hydroxy acid is prepared by reacting 1,7-octadiyne in THF which was treated with HMPA, BuLi, and 11-bromoundecanol to give 1,30-hydroxytriaconta-12,18-diyne in low yield. The diyne was then hydrogenated to give 1,30-tricotanediol, in which one hydroxy group was protected and the other hydroxy group was oxidized to a carboxylic acid. This last step in the process disclosed in the '281 document is an unselective protection and gives desired intermediate in low yield: the process also uses expensive raw materials.
Heslinga and Pabon describe .omega.-hydroxy docosanoic acid synthesis in "Synthesis of the linoleic acid esters of some unsaturated long-chain.omega.-hydroxy fatty acids," Recl. Trav. Pays-Bas, 103, pp. 348-351 (1984). Their synthesis requires the use of 11-undecynoic acid, which can be obtained by reacting sodium acetylide with 9-iodononanoic acid. 11-undecynoic acid is converted to 11-bromoundecynoic acid using hydrobromination. THP protected acetylide, 1-0-tetrahydropyranyl-10-undecyne is prepared by using tetrahydropyran as protecting group as described by Parham et al., J. Am. Chem. Soc. (1948) 70, 4187, and subsequently is reacted with 11-bromo-10-undecynoic acid to give a diacetylene adduct. Hydrogenation followed by a deprotection of THP gives .omega.-hydroxy docosanoic acid.
Yokota et al. (U.S. Pat. No. 5,191,096) discloses a process of subjecting an ester or a di-carboxylic acid compound to a catalytic hydrogenation. Dioic acid is disclosed as a suitable starting material. Unfortunately, only a few dioic acids are commercially available. Hirosi et al. (U.S. Pat. No. 5,099,036) discloses a process of making .alpha.-(.omega.-cyanoalkanoyl)-.gamma.-butrylactone. The processes disclosed by Yokota and Hirosi consist of complicated and multistage production steps, and expensive raw materials are used, so that the production cost is unfavorable. The Hirosi process is also limited to shorter carbon chain length (i.e., 7 to 12 carbons) due to poor availability of raw materials and cyanoalkanoyl materials.
The above-discussed processes have serious shortcomings: they require multiple steps and expensive raw materials.
Naturally occuring .omega.-hydroxy docosanoic acid has been isolated from the outer bark of Betula verrucosa Ehrh. by hydrolysis, methanolysis, and alkali fusion. About 14% of .omega.-hydroxy docosanoic acid is identified in the dried outer barks. .omega.-hydroxy docosanoic acid was also isolated from a typical cork tree. Obtaining .omega.-hydroxy acid from natural sources is tedious and expensive.
As evidenced by the art discussed above, there is a need for an alternative, commercially viable process of making an .omega.-hydroxy acid.
Accordingly, it is an object of the present invention to provide a novel process of preparing an .omega.-hydroxy acid while avoiding the disadvantages of prior art.
These and other objects of the invention will become more apparent from the detailed description and examples that follow.